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INFLAMMATION AND IMMUNOPHARMACOLOGY

Preclinical Profile of Ciclesonide, a Novel Corticosteroid for the Treatment of Asthma

Pharmacology Department, Aventis Pharma, Dagenham, Essex, United Kingdom (M.G.B., S.W., S.U., C.H.B., E.-B.H., S.E.W., M.L.F.); Respiratory Pharmacology Group, Imperial College School of Medicine at the National Heart and Lung Institute, London, United Kingdom (M.G.B.); Altana Pharma, Konstanz, Germany (D.S.B., M.S.); and Aventis Pharma, Bridgewater, New Jersey (E.-B.H., S.U.)

Ciclesonide is a novel, inhaled corticosteroid under development for the treatment of asthma. Ciclesonide is activated to desisobutyryl-ciclesonide (des-CIC) in the lungs to provide potent anti-inflammatory activity. The investigations herein compared the activity of ciclesonide with fluticasone in animal models to assess efficacy/potency as an airway anti-inflammatory and the comparative side effect potential to consider the therapeutic ratio of each compound. In radioligand binding assays, des-CIC and fluticasone exhibited comparable high-affinity binding to the glucocorticoid receptor, whereas ciclesonide exhibited 100-fold less binding affinity. In the Brown Norway rat model of antigen-induced airway eosinophilia and in a model of Sephadex-induced lung edema, ciclesonide and fluticasone exhibited comparable efficacy. Interestingly, following 7-day intratracheal administration, ciclesonide elicited adrenal involution with a potency that was 44-fold less than fluticasone. Furthermore, ciclesonide was 22-fold less active than fluticasone in eliciting hypoplasia of the femoral growth plate. These data support the concept that ciclesonide acts as a parent compound that, when delivered to the airways, can be transformed into the active metabolite des-CIC, resulting in local high anti-inflammatory activity. Furthermore, ciclesonide possesses equivalent anti-inflammatory efficacy through pulmonary activation with a significantly improved safety profile in preclinical animal models compared with fluticasone.

Address correspondence to: Professor Maria G. Belvisi, Respiratory Pharmacology, Department of Cardiothoracic Surgery, Imperial College School of Medicine at the National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK. E-mail: m.belvisi{at}imperial.ac.uk